Warfarin sodium, known by the chemical name 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2one sodium salt, has the structure represented by Formula 1:
Warfarin sodium has a molecular weight of 360.37 g/mol; is known to crystallize only as a clathrate with isopropyl alcohol as the guest molecule; and is monoclinic in the crystalline form.
Warfarin sodium is a well-established, widely-used anticoagulant that acts by blocking the synthesis of vitamin K-dependent coagulation factors (II, VII, IX, and X). There are a number of related conditions for which warfarin sodium is prescribed such as venous thrombosis, pulmonary embolism, myocardial infarction, and progressive stroke. Warfarin is administered as a racemic mixture of two enantiomers which have markedly different metabolism and activity. The t1/2 of racemic warfarin ranges from 40 to 60 hours. Oral absorption of warfarin is rapid (2-6 hours) and extensive (F≈1). Warfarin is highly bound to albumin in plasma (≈99%) and has apparent Vd of 0.13 L/kg. Warfarin has a low hepatic extraction ratio and elimination occurs almost entirely by metabolism (>99%). Warfarin is known to have both pharmacokinetic and pharmacodynamic interactions with a number of drugs including barbiturates, rifampicin, cimetidine, phenylbutazone, and salicylate.
Currently, warfarin sodium for oral administration is provided only in tablet form, and no warfarin sodium product is available in oral liquid form.
Even the warfarin sodium products for intravenous injection currently available in the market are not provided in liquid form but as lyophilized powder that is reconstituted with sterile water immediately prior to injection. For example, Coumadin®, a warfarin sodium drug produced by Bristol-Myers Squibb Company, is available for intravenous injection but is provided as lyophilized powder in a vial. The powder is reconstituted with sterile water for intravenous injection, and must be used within 4 hours of reconstitution because the warfarin sodium formulation is chemically and physically stable only for 4 hours at room temperature. After reconstitution, the warfarin sodium formulation must be stored at controlled room temperature (15-30° C.), and any unused solution must be discarded.
U.S. Pat. No. 2,999,049 also discloses warfarin sodium composition for intravenous or intramuscular injection. This reference is directed to providing a intravenous or intramuscular composition containing both warfarin sodium and heparin sodium, and, while disclosing a liquid form of the composition as well as a dry lyophilized form, the reference also discloses that a solid product substantially free of moisture is preferred for overall stability during long periods of storage.
Thus, there is no currently available liquid form of warfarin sodium that can be orally administered. Further, the available injectable form of warfarin sodium presents a number of disadvantages. Not only is it difficult to administer since it requires reconstitution with water before use, but warfarin sodium currently available for intravenous injection must also be carefully monitored during administration to ensure sterility. For instance, reconstitution must be carried out under sterile conditions, the reconstituted Solution must be inspected for presence of particulate matter or discoloration, and sterility must be maintained throughout the injection procedure. In addition, administration of the existing injectable warfarin sodium solution is constrained by time because the solution must be used within 4 hours of reconstitution, and may involve additional waste since the vial containing lyophilized powder of warfarin sodium cannot be used multiple times and unused portions of reconstituted solution must be discarded.
In view of the current state of the art, a liquid form of warfarin sodium that is stable in the long term and does not require reconstitution is desired. Such stable warfarin sodium liquid would not only be safer to administer than the conventional injectable warfarin sodium, but would also be more user-friendly and easier to administer and therefore would help eliminate mistakes associated with administration of the existing warfarin sodium product.
Further, a stable warfarin sodium liquid form that can be orally administered is desired, especially since the dosage form of warfarin sodium (solution or tablet) does not seem to significantly affect plasma levels. The amount absorbed is also not affected by food, volume of fluid ingested, or dosage form. Until now, however, the difficulty of producing a stable liquid form of warfarin sodium has prevented commercialization of the drug in oral liquid form despite its potential advantages over the conventional tablet form for providing easy administration even to patients who have trouble swallowing tablets. A drinkable form of warfarin sodium is further advantageous over intravenous injection, since it is much more convenient to use and can be administered without a physician's supervision or special equipments.
Hence, what is needed is a stable liquid form of warfarin sodium that can be adapted for parenteral as well as oral administration. The present invention addresses the problems of the prior art by providing a liquid warfarin sodium formulation that is stable in the long term and can be conveniently administered.